Immune recognition of pathogens and tumors involves both innate and adaptive arms of the immune system. Natural Killer T (NKT) cells are innate lymphocytes implicated in the control of autoimmunity, and resistance to tumors and pathogens. In contrast to conventional CD4/CD8+ T cells that recognize peptide antigens, NKT cells respond to glycolipid ligands in the context of CD1d. α-galactosyl ceramide (α-GalCer), first isolated from a marine sponge, is a synthetic ligand that is effectively presented on CD1d molecules to both human and murine NKT cells. Activation of NKT cells in mice by injection of α-GalCer is associated with a rapid release of cytokines within hours. Stimulation of NKT cells is followed by downstream activation of NK cells, dendritic cells (DCs) and T cells. α-GalCer mediated NKT activation has been shown to mediate tumor regression in several mouse models. The anti-tumor effects of NKT cells have been demonstrated to be due to several mechanisms including enhancement of immune effectors, as well as anti-angiogenesis. NKT cells also contribute to resistance against spontaneous and carcinogen-induced tumors in mice.
Human NKT cells have been analyzed on the basis of their expression of an invariant T cell receptor (Vα24/Vβ11) and their binding to CD1d-α-GalCer multimers. Human Vα24+ NKT cells can mediate anti-tumor effects in vitro, and a deficiency of NKT cells, or defects in their function, have been described in cancer patients. The availability of α-GalCer as the pharmaceutical grade drug KRN-7000 (Kirin Breweries, Japan) has led to attempts to boost NKT cells in vivo in patients with advanced cancer or healthy volunteers. However, the injection of KRN-7000 alone, or KRN-7000 loaded immature DCs, only leads to transient NKT activation in some individuals.